INOMax®, (nitric oxide) (available from Ikaria, Inc. in Hampton, N.J.) for inhalation is an approved drug product for the treatment of term and near-term (<34 weeks gestation) neonates having hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension (INOmax label SPC-LBL 0303 R 9 herein incorporated by reference).
Data from several animal models indicate that nitric oxide is required for normal lung development. In vivo, nitric oxide is synthesized from L-arginine by a family of nitric oxide synthase (NOS) enzymes. The constitutive isoenzymes endothelial nitric oxide synthase (eNOS) and neuronal nitric oxide synthase (nNOS) mediate nitric oxide in mammals. A cytokine-inducible isoform (iNOS) produces NO as an immune defense mechanism. It has been shown that mice genetically deficient in eNOS are susceptible to mild neonatal hypoxia, with evidence of alveolar simplification and a reduction in vascular volume that is not seen in wild-type mice. (Balasubramaniam et al. (2003) Amer. J. Physiol.—Lung Cellular and Molecular Physiology 284:L964-L971). Administration of inhaled nitric oxide in mice with eNOS deficiency stimulated alveolar and vascular growth.
Survival among preterm infants has improved over time due to improvements in the ability to enhance fetal lung maturation and to manage respiratory distress syndrome. Chronic lung disease, i.e., bronchopulmonary dysplasia (BPD), is now the most significant long-term pulmonary complication. BPD required prolonged hospitalization and is associated with long-term pulmonary and neurodevelopmental problems. In its more severe form, BPD is associated with inflammation, pulmonary hypertension and increased airway resistance, and abnormalities in lung development.
Inhaled nitric oxide (iNO) has been used as a therapy for pulmonary hypertension in full-term infants, but its efficacy for prevention of BPD in premature infants is not clearly established. Published studies report both a benefit (i.e. decreased incidence of BPD) and a lack of such benefit. These studies differ substantially in the preterm infant patient populations studied, the treatment protocols, and determination of outcome. Such mixed results suggest that the therapeutic response is variable due variations in the patient population. The factors contributing to this variability have not been identified and are not understood. There is therefore a need for methods for identifying a subpopulation of premature infants at risk for developing BPD that is more likely to have a therapeutic response to iNO, as evidenced by prevention of long term pulmonary complications such as BPD. Identifying this subpopulation may also avoid administration of iNO to a subpopulation not likely to develop BPD. The present invention addresses this need.